This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity is a worldwide health epidemic. Among the current therapies for obesity is Roux-en-Y gastric bypass (RYGB), which has proven to be very effective. Recent studies have revealed, unexpectedly, that RYGB works primarily by altering the physiological control of energy balance and body fat storage. It affects a wide variety of physiological systems, including the regulation of ingestive behavior, energy expenditure and glucose homeostasis. Moreover, the beneficial effects of this operation on diabetes and other metabolic disorders appear to include mechanisms independent of weight loss or diminished food intake. For such studies, we are examining the physiological effects of RYGB in the Rhesus macaque, a species of NHP that, like many humans, is susceptible to the weight gain and diabetes-promoting effects of a high fat diet. The aims of the project are (1) to establish a model of RYGB in obese Rhesus macaques and to characterize its effects on food intake, ingestive behavior, food preference and energy expenditure, phenotypes that appear highly responsive to RYGB in humans and rodents;(2) to characterize the effects of RYGB on glucose homeostasis and determine the mechanisms of these effects and the degree to which they are dependent on changes in food intake or body weight;(3) to characterize the effect of RYGB on the hypothalamic circuitry regulating ingestive behavior and energy balance;and (4) to examine the broad metabolic response to RYGB through gene expression and metabolic profiling of peripheral and portal venous blood, selected brain nuclei, pancreatic islets, liver and muscle.